CN105111125B - A kind of synthetic method of pharmaceutical intermediate condensed hetero ring ketone compounds - Google Patents
A kind of synthetic method of pharmaceutical intermediate condensed hetero ring ketone compounds Download PDFInfo
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- CN105111125B CN105111125B CN201510634218.7A CN201510634218A CN105111125B CN 105111125 B CN105111125 B CN 105111125B CN 201510634218 A CN201510634218 A CN 201510634218A CN 105111125 B CN105111125 B CN 105111125B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/36—Oxygen atoms in position 3, e.g. adrenochrome
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- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention relates to a kind of synthetic method of condensed hetero ring ketone compounds shown in lower formula (III), methods described includes：At room temperature, lower formula (I) compound, lower formula (II) compound, catalyst, auxiliary agent and alkali are sequentially added into organic solvent, then heat to 70 80 DEG C and be sufficiently stirred for reaction 6 10 hours, so as to obtain the formula (III) compoundWherein, R1For C1‑C6Alkyl or phenyl unsubstituted or with substituent；R2For C1‑C6Alkoxy, C6‑C12Alkyl or phenyl.Comprehensive selection and coordination of the methods described by catalyst, auxiliary agent, alkali and organic solvent, generate unexpected effect in high yield, and the process time is shorter, be conducive to meeting industrial low energy consumption demand, with extensive market prospects, there are good industrial applications potentiality in organic chemical synthesis field especially medicine intermediate synthesis field.
Description
Technical field
The present invention relates to a kind of synthetic method of ketone compounds, relate more particularly to a kind of pharmaceutical intermediate condensed hetero ring ketone
The synthetic method of class compound, belongs to organic synthesis especially medicine intermediate synthesis field.
Background technology
In organic chemical synthesis especially medicine intermediate synthesis technical field, heterocyclic ketones have important work
For and status, it can generally act on the synthetic intermediate of final medicine to use.
Just because of the such important effect of such compound, people synthesize to it has carried out substantial amounts of research, and obtains
Some achievements, for example：
(" the New Synthesis of such as Franca M.Corderoby Ethylene Extrusion
From Spirocyclopropane Isoxazolidines ", J.Am.Chem.Soc., 2000,122,8075-8076) report
The method that a kind of use N-O bond cleavages point prepare Beta-aminoketones compound, its reaction equation is as follows：
(" the A conjugate addition/dipolar-cycloaddition cascade such as Andrew C.Flick
sequence for the synthesis of(±)-cylindricine C”,Tetrahedron Letters,2010,
66,3643-3650) a kind of synthetic method method of heterocyclic ketones is also reported, its reaction equation is as follows：
As described above, there is the synthetic method of some heterocyclic ketones in the prior art, but for such change
The novel method for synthesizing of compound, still suffers from the necessity for continuing to study.
The present inventor proves by the research and improvement to a large amount of academic informations, and by the experiment of science, so as to carry
Go out a kind of synthetic method of pharmaceutical intermediate condensed hetero ring ketone compounds, it uses the combination of multicomponent composite catalyzing reagent,
Reaction process is improved, has promoted reaction to carry out so that reaction yield is significantly improved, and shows extensive prospects for commercial application.
The content of the invention
In order to seek the novel method for synthesizing of heterocyclic ketones, present inventor has performed in-depth study and exploration,
After enough creative works have been paid, so as to complete the present invention.
Specifically, technical scheme and content are related to condensed hetero ring ketone compounds shown in a kind of lower formula (III)
Synthetic method, methods described includes：At room temperature, lower formula (I) compound, lower formula (II) chemical combination are sequentially added into organic solvent
Thing, catalyst, auxiliary agent and alkali, then heat to 70-80 DEG C and are sufficiently stirred for reaction 6-10 hours, post-treated, so as to obtain
Formula (III) compound,
Wherein, R1For C1-C6Alkyl or phenyl unsubstituted or with substituent, the substituent are nitro or C1-C6
Alkoxy；
R2For C1-C6Alkoxy, C6-C12Alkyl or phenyl.
In the synthetic method of the present invention, the C1-C6The implication of alkyl refers to the straight chain with 1-6 carbon atom
Or branched alkyl, for example can be methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, uncle in non-limiting manner
Butyl, n-pentyl, isopentyl or n-hexyl etc..
In the synthetic method of the present invention, the C1-C6The implication of alkoxy refers to above-mentioned implication
C1-C6The group that alkyl is obtained after being connected with oxygen atom.
In the synthetic method of the present invention, the C6-C12The implication of alkyl refers to straight with 6-12 carbon atom
Chain or branched alkyl, for example can be n-hexyl, n-heptyl, n-octyl, n-nonyl, positive decyl, n-undecane base in non-limiting manner
Or dodecyl etc..
In the synthetic method of the present invention, the catalyst is Ru3(CO)12With the mixture of porphyrin, wherein Ru3
(CO)12Mol ratio with porphyrin is 1:0.5.
In the synthetic method of the present invention, the auxiliary agent is the mixed of 2- flurophenyl boronic acid pinacol esters and organosilan
Compound, the wherein mol ratio of 2- flurophenyl boronic acids pinacol ester and organosilan are 1:0.2-0.5, for example, can be 1:0.2、1:
0.4 or 1:0.5.
Wherein, the organosilan be selected from dimethyl diethylsilane, diphenyl silane, dimethyl diethoxy silicon
Any one in alkane, 1,2- bis- (triethoxy silicon substrate) ethane, most preferably 1,2- bis- (triethoxy silicon substrate) ethane.
In the synthetic method of the present invention, the alkali is NaOH, sodium carbonate, potassium carbonate, triethylene diamine, tetramethyl
Any one in ethylenediamine (TMEDA), N, N'- dimethyl-ethylenediamines (DMEDA), DIPEA (DIPEA), most
Preferably DMEDA.
In the synthetic method of the present invention, the organic solvent is diethylene glycol dimethyl ether with being selected from toluene, benzene, second
Any of alcohol, acetonitrile, 1,4- dioxane, DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide (DMSO)) mixing
Thing, wherein diethylene glycol dimethyl ether are with being selected from toluene, benzene, ethanol, acetonitrile, Isosorbide-5-Nitrae-dioxane, DMF (N, N- dimethyl formyls
Amine), any of DMSO (dimethyl sulfoxide (DMSO)) volume ratio be 1:2-3.
Wherein, the organic solvent is most preferably mixture (diethylene glycol dimethyl ether and the second of diethylene glycol dimethyl ether and acetonitrile
The volume ratio of nitrile is also 1 certainly:2-3).
Wherein, the consumption of the organic solvent does not have strict restriction, and those skilled in the art can be according to actual conditions
Suitable selection is carried out with determining, such as its consumption size no longer carries out detailed to facilitate reaction to carry out and post-process, herein
Thin description.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and formula (II) compound is 1:
1.5-2, for example, can be 1:1.5、1:1.7、1:1.9 or 1:2.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and catalyst is 1:0.06-0.1,
The mole dosage of i.e. described formula (I) compound and the Ru for constituting the catalyst3(CO)12With the ratio of the mole dosage of both porphyrins
For 1:0.06-0.1, for example, can be 1:0.06、1:0.08 or 1:0.1.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and auxiliary agent is 1:0.3-0.5, i.e.,
The mole dosage of formula (I) compound and the 2- flurophenyl boronic acid pinacol esters and both organosilans for constituting the auxiliary agent
The ratio of mole dosage is 1:0.3-0.5, for example, can be 1:0.4、1:0.4 or 1:0.5.
In the synthetic method of the present invention, the mol ratio of formula (I) compound and alkali is 1:1-2, for example can be
1:1、1:1.5 or 1:2.
In the synthetic method of the present invention, the post processing after reaction terminates is as follows：After completion of the reaction, by reaction system
Room temperature is naturally cooled to, then regulation system pH value is 6.5-7, and washing is then fully vibrated with deionized water, chloroform is added
Extraction 2-3 times, merges organic phase, is dried with anhydrous magnesium sulfate, vacuum distillation, residue crosses 300-400 mesh silica gel column chromatographies, with
Volume ratio is 1:2 ethyl acetate and the mixture of acetone are leacheate, and TLC detection elution terminals collect eluent, evaporation is removed
Solvent is removed, so as to obtain the formula (III) compound.
As described above, the invention provides a kind of synthesis side for the condensed hetero ring ketone compounds that can be used as pharmaceutical intermediate
Method, comprehensive selection and coordination of the methods described by catalyst, auxiliary agent, alkali and organic solvent generates unexpected high receipts
The effect of rate, and the process time is shorter, is conducive to meeting industrial low energy consumption demand, with extensive market prospects,
Organic chemical synthesis field especially medicine intermediate synthesis field has good industrial applications potentiality.
Embodiment
Below by specific embodiment, the present invention is described in detail, but the purposes of these exemplary embodiments and
Purpose only be used for enumerate the present invention, not to the present invention real protection scope constitute it is any type of it is any limit, it is more non-will
Protection scope of the present invention is confined to this.
Embodiment 1
At room temperature, (it is volume ratio 1 to appropriate organic solvent:2 diethylene glycol dimethyl ether and the mixture of acetonitrile) in successively
It (is 4mmol Ru to add formula (I) compound on 100mmol, the upper formula (II) compounds of 150mmol, 6mmol catalyst3(CO)12With
The mixture of 2mmol porphyrins), 30mmol auxiliary agents (be 25mmol 2- flurophenyl boronic acid pinacol esters and 5mmol 1,2- bis- (three
Ethyl-silicone) ethane mixture) and 100mmol alkali DMEDA, then heat to 70 DEG C and be sufficiently stirred at such a temperature anti-
Answer 10 hours；
After completion of the reaction, reaction system is naturally cooled into room temperature, then regulation system pH value is 6.5-7, is then spent
Ionized water fully vibrates washing, adds chloroform and extracts 2-3 times, merges organic phase, dried with anhydrous magnesium sulfate, vacuum distillation,
Residue crosses 300-400 mesh silica gel column chromatographies, using volume ratio as 1:2 ethyl acetate and the mixture of acetone are leacheate, TLC
Detection elution terminal, collection eluent, evaporation of solvent, so as to obtain formula (III) compound, yield is 96.7%.
1H NMR(CDCl3,400MHz):δ0.76-0.87(m,3H),1.08-1.34(m,8H),1.76-2.00(m,2H),
2.88 (d, J=17.6Hz, 1H), 3.65 (d, J=17.4Hz, 1H), 5.76 (s, 1H), 6.73-6.82 (m, 1H), 6.87 (d, J
=8.3Hz, 1H), 7.39-7.52 (m, 3H), 7.53-7.64 (m, 2H), 7.89-7.98 (m, 2H).
Embodiment 2
At room temperature, (it is volume ratio 1 to appropriate organic solvent:2.5 diethylene glycol dimethyl ether and the mixture of acetonitrile) according to
Formula (I) compound, the upper formula (II) compounds of 175mmol, 7.5mmol catalyst (are 5mmol Ru on secondary addition 100mmol3
(CO)12With the mixture of 2.5mmol porphyrins), 39mmol auxiliary agents (be 26mmol 2- flurophenyl boronic acid pinacol esters and 13mmol
The mixture of 1,2- bis- (triethoxy silicon substrate) ethane) and 150mmol alkali DMEDA, then heat to 75 DEG C and at such a temperature
It is sufficiently stirred for reaction 8 hours；
After completion of the reaction, reaction system is naturally cooled into room temperature, then regulation system pH value is 6.5-7, is then spent
Ionized water fully vibrates washing, adds chloroform and extracts 2-3 times, merges organic phase, dried with anhydrous magnesium sulfate, vacuum distillation,
Residue crosses 300-400 mesh silica gel column chromatographies, using volume ratio as 1:2 ethyl acetate and the mixture of acetone are leacheate, TLC
Detection elution terminal, collection eluent, evaporation of solvent, so as to obtain formula (III) compound, yield is 96.9%.
1H NMR(CDCl3,400MHz):δ 0.89 (t, J=6.1Hz, 3H), 1.12-1.27 (m, 14H), 1.35-1.55
(m, 2H), 2.25-2.45 (m, 2H), 2.74 (d, J=17.8Hz, 1H), 3.73 (d, J=17.8Hz, 1H), 6.32 (s, 1H),
6.82 (t, J=7.4Hz, 1H), 6.99 (d, J=8.2Hz, 1H), 7.44-7.60 (m, 2H), 7.71-7.84 (m, 2H), 8.09-
8.21(m,2H)。
Embodiment 3
At room temperature, (it is volume ratio 1 to appropriate organic solvent:3 diethylene glycol dimethyl ether and the mixture of acetonitrile) in successively
It (is 6.6mmol Ru to add formula (I) compound on 100mmol, the upper formula (II) compounds of 200mmol, 9.9mmol catalyst3
(CO)12With the mixture of 3.3mmol porphyrins), 50mmol auxiliary agents (for 37.5mmol 2- flurophenyl boronic acid pinacol esters with
The mixture of 12.5mmol1,2- bis- (triethoxy silicon substrate) ethane) and 200mmol alkali DMEDA, then heat to 80 DEG C and
Reaction 6 hours is sufficiently stirred at this temperature；
After completion of the reaction, reaction system is naturally cooled into room temperature, then regulation system pH value is 6.5-7, is then spent
Ionized water fully vibrates washing, adds chloroform and extracts 2-3 times, merges organic phase, dried with anhydrous magnesium sulfate, vacuum distillation,
Residue crosses 300-400 mesh silica gel column chromatographies, using volume ratio as 1:2 ethyl acetate and the mixture of acetone are leacheate, TLC
Detection elution terminal, collection eluent, evaporation of solvent, so as to obtain formula (III) compound, yield is 96.4%.
1H NMR(CDCl3,400MHz):δ 0.83-0.92 (m, 3H), 1.24 (br s, 14H), 1.50 (t, J=6.9Hz,
2H), 2.32-2.43 (m, 2H), 2.99 (d, J=16.9Hz, 1H), 3.64 (d, J=17.1Hz, 1H), 3.85 (s, 3H), 6.13
(br s, 1H), 6.76-6.86 (m, 2H), 6.86-7.01 (m, 2H), 7.19-7.32 (m, 2H), 7.41 (td, J=7.6,
1.3Hz,1H),7.66-7.74(m,1H)。
Embodiment 4
At room temperature, (it is volume ratio 1 to appropriate organic solvent:2.5 diethylene glycol dimethyl ether and the mixture of acetonitrile) according to
Formula (I) compound, the upper formula (II) compounds of 160mmol, 7.2mmol catalyst (are 4.8mmol Ru on secondary addition 100mmol3
(CO)12With the mixture of 2.4mmol porphyrins), 40mmol auxiliary agents (be 32mmol 2- flurophenyl boronic acid pinacol esters and 8mmol
The mixture of 1,2- bis- (triethoxy silicon substrate) ethane) and 175mmol alkali DMEDA, then heat to 75 DEG C and at such a temperature
It is sufficiently stirred for reaction 7 hours；
After completion of the reaction, reaction system is naturally cooled into room temperature, then regulation system pH value is 6.5-7, is then spent
Ionized water fully vibrates washing, adds chloroform and extracts 2-3 times, merges organic phase, dried with anhydrous magnesium sulfate, vacuum distillation,
Residue crosses 300-400 mesh silica gel column chromatographies, using volume ratio as 1:2 ethyl acetate and the mixture of acetone are leacheate, TLC
Detection elution terminal, collection eluent, evaporation of solvent, so as to obtain formula (III) compound, yield is 97.1%.
1H NMR(CDCl3,400MHz):δ0.78-0.87(m,3H),1.07-1.28(m,11H),1.71-1.84(m,
2H), 2.53 (d, J=15.7Hz, 1H), 2.71 (d, J=15.7Hz, 1H), 4.02-4.14 (m, 2H), 5.35 (br s, 1H),
6.74-6.88 (m, 2H), 7.44 (ddd, J=8.3,7.1,1.3Hz, 1H), 7.58 (d, J=7.8Hz, 1H).
Embodiment 5-12
Embodiment 5-8：Except by catalyst therein replace with consumption be the total consumption of original two kinds of components one-component Ru3
(CO)12Outside, other operations are constant, so as to implement embodiment 1-4 successively, sequentially obtain embodiment 5-8.
Embodiment 9-12：Except by catalyst therein replace with consumption be the total consumption of original two kinds of components one-component porphin
Outside quinoline, other operations are constant, so as to implement embodiment 1-4 successively, sequentially obtain embodiment 9-12.
As a result it see the table below 1.
Table 1
As can be seen here, when using one-component as catalyst, yield has significant reduction, especially only makes
When using porphyrin, the meaning of research and the possibility of production have been lost.This proves Ru3(CO)12Uniqueness can be played with porphyrin
Concerted catalysis is acted on, so as to obtain the excellent technique effect of the present invention, this is unexpected.
Embodiment 13-32
Embodiment 13-16：Except 1,2- bis- (triethoxy silicon substrate) ethane in auxiliary agent is replaced with into dimethyl diethyl silicon
Outside alkane, other operations are constant, so as to implement embodiment 1-4 successively, sequentially obtain embodiment 13-16.
Embodiment 17-20：Except 1,2- bis- (triethoxy silicon substrate) ethane in auxiliary agent is replaced with outside diphenyl silane, its
Its operation is constant, so as to implement embodiment 1-4 successively, sequentially obtains embodiment 17-20.
Embodiment 21-24：Except 1,2- bis- (triethoxy silicon substrate) ethane in auxiliary agent is replaced with into dimethyl diethoxy
Outside silane, other operations are constant, so as to implement embodiment 1-4 successively, sequentially obtain embodiment 21-24.
Embodiment 25-28：Except by auxiliary agent therein replace with consumption be the total consumption of original two kinds of components one-component 2-
Outside flurophenyl boronic acid pinacol ester, other operations are constant, so as to implement embodiment 1-4 successively, sequentially obtain embodiment 25-
28。
Embodiment 29-32：Except by auxiliary agent therein replace with consumption be the total consumption of original two kinds of components one-component 1,
Outside 2- bis- (triethoxy silicon substrate) ethane, other operations are constant, so as to implement embodiment 1-4 successively, sequentially implemented
Example 29-32.
As a result 2 be see the table below.
Table 2
Note：" -- " represents to be not present.
As can be seen here, in the organo-silicon compound of adjuvant component, 1,2- bis- (triethoxy silicon substrate) ethane has best
Effect；It can also be seen that when 2- flurophenyl boronic acid pinacol esters or 1,2- bis- (triethoxy silicon substrate) ethane is used alone,
Yield has significant reduction.This demonstrate that only simultaneously using 2- flurophenyl boronic acid pinacol esters and the mixture of organosilan
As auxiliary agent, the remarkable result of the present invention could be obtained, collaboration facilitation can be played between both components by also demonstrating.
Embodiment 33-38
In addition to Different Alkali in use following table, other operations are constant, so as to correspond to different embodiments and be implemented
Example 33-38, specific used alkali, embodiment corresponding relation and products collection efficiency see the table below 3.
Table 3
As can be seen here, in all alkali, DMEDA has best effect, and the effect of triethylene diamine is also preferable, but its
Its alkali then has obvious reduction.
Embodiment 39-44
Come in addition to replacing acetonitrile, other operations are constant (diethylene glycol dimethyl is only used only in organic solvent in using following table
The mixture of ether and solvent composition in following table is used as the organic solvent), so as to correspond to different embodiments and be implemented
Example 39-44, specific used solvent composition, embodiment corresponding relation and the products collection efficiency for replacing acetonitrile see the table below 4.
Table 4
As can be seen here, when using other solvents are not to replace acetonitrile therein when, products collection efficiency has obvious reduction, especially
It is benzene and toluene, is reduced the most obvious.This demonstrate that the mixture of diethylene glycol dimethyl ether and acetonitrile has best solvent effect
Really.
In order to further investigate the influence of solvent, applicant is investigated using one-component respectively, used list
One component, embodiment corresponding relation and products collection efficiency see the table below 5.
Table 5
As can be seen here, when using one-component as solvent, yield equally has significant reduction, especially individually makes
During with diethylene glycol dimethyl ether or acetonitrile, yield is significantly reduced.It can also be seen that embodiment 45-50 and embodiment 39-44 phases
Than yield is more or less the same, and this is proved using one-component or diethylene glycol dimethyl ether and the two part solvent of these components, to anti-
Should result influence it is little.Although but it was unexpectedly determined that yield is respectively when diethylene glycol dimethyl ether or acetonitrile is used alone
90.4% and 87.2%, but when the combination using both, then yield, which has, significantly improves (see the yield of embodiment -14),
Unexpected technique effect can be produced this further demonstrates both.
As described above, the invention provides a kind of synthesis side for the condensed hetero ring ketone compounds that can be used as pharmaceutical intermediate
Method, comprehensive selection and coordination of the methods described by catalyst, auxiliary agent, alkali and organic solvent generates unexpected high receipts
The effect of rate, and the process time is shorter, is conducive to meeting industrial low energy consumption demand, with extensive market prospects,
Organic chemical synthesis field especially medicine intermediate synthesis field has good industrial applications potentiality.
It should be appreciated that the purposes of these embodiments is merely to illustrate the present invention and is not intended to limitation protection model of the invention
Enclose.In addition, it will also be appreciated that after the technology contents of the present invention have been read, those skilled in the art can make each to the present invention
Change, modification and/or variation are planted, all these equivalent form of values equally fall within the guarantor that the application appended claims are limited
Within the scope of shield.
Claims (6)
1. a kind of synthetic method of condensed hetero ring ketone compounds shown in lower formula (III), methods described includes：At room temperature, to organic
Lower formula (I) compound, lower formula (II) compound, catalyst, auxiliary agent and alkali are sequentially added in solvent, 70-80 DEG C is then heated to
And be sufficiently stirred for reacting 6-10 hours, so that the formula (III) compound is obtained,
Wherein, R1For C1-C6Alkyl or phenyl unsubstituted or with substituent, the substituent are nitro or C1-C6Alcoxyl
Base；
R2For C1-C6Alkoxy, C6-C12Alkyl or phenyl；
The catalyst is Ru3(CO)12With the mixture of porphyrin, wherein Ru3(CO)12Mol ratio with porphyrin is 1:0.5；
The auxiliary agent is the mixture of 2- flurophenyl boronic acid pinacol esters and organosilan, wherein 2- flurophenyl boronic acids pinacol ester
Mol ratio with organosilan is 1:0.2-0.5；
The organosilan is selected from dimethyl diethylsilane, diphenyl silane, dimethyldiethoxysilane, 1,2- bis-
Any one in (triethoxy silicon substrate) ethane；
The alkali is N, N'- dimethyl-ethylenediamines；
The organic solvent is the mixture of diethylene glycol dimethyl ether and acetonitrile, and the volume ratio of diethylene glycol dimethyl ether and acetonitrile is 1:2-
3。
2. synthetic method as claimed in claim 1, it is characterised in that：The organosilan is 1,2- bis- (triethoxy silicon substrate)
Ethane.
3. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound is rubbed with formula (II) compound
You are than being 1:1.5-2.
4. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound and the mol ratio of catalyst are
1:0.06-0.1。
5. synthetic method as claimed in claim 1, it is characterised in that：Formula (I) compound and the mol ratio of auxiliary agent are 1:
0.3-0.5。
6. the synthetic method as described in claim any one of 1-5, it is characterised in that：Mole of formula (I) compound and alkali
Than for 1:1-2.
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